Zinc-air batteries(ZABs)are promising energy storage systems because of high theoretical energy density,safety,low cost,and abundance of zinc.However,the slow multi-step reaction of oxygen and heavy reliance on noble-...Zinc-air batteries(ZABs)are promising energy storage systems because of high theoretical energy density,safety,low cost,and abundance of zinc.However,the slow multi-step reaction of oxygen and heavy reliance on noble-metal catalysts hinder the practical applications of ZABs.Therefore,feasible and advanced non-noble-metal elec-trocatalysts for air cathodes need to be identified to promote the oxygen catalytic reaction.In this review,we initially introduced the advancement of ZABs in the past two decades and provided an overview of key developments in this field.Then,we discussed the work-ing mechanism and the design of bifunctional electrocatalysts from the perspective of morphology design,crystal structure tuning,interface strategy,and atomic engineering.We also included theoretical studies,machine learning,and advanced characterization technologies to provide a comprehensive understanding of the structure-performance relationship of electrocatalysts and the reaction pathways of the oxygen redox reactions.Finally,we discussed the challenges and prospects related to designing advanced non-noble-metal bifunctional electrocatalysts for ZABs.展开更多
Colorectal cancer(CRC)is a common cancer with high morbidity and mortality rates.Its occurrence and development are determined by many factors,including genetics,the environment,lifestyle,and so on.The occurrence of C...Colorectal cancer(CRC)is a common cancer with high morbidity and mortality rates.Its occurrence and development are determined by many factors,including genetics,the environment,lifestyle,and so on.The occurrence of CRC is often accompanied by changes in the intestinal microenvironment.Numerous studies have focused on the association between dietary patterns,dietary components,and CRC now.This article reviews five different dietary patterns:the Western diet,the Mediterranean diet,the ketogenic diet,the Dietary Approaches to Stop Hypertension diet,and fasting,and themechanistic associations between their food components and CRC.The finding can provide a reference for further studies on the association between different dietary patterns and CRC and will help clinicians formulate reasonable and feasible dietary interventions.展开更多
A three dimensional finite element program incorporating actually measured vertical tire-pavement contact pressure(TPCP) was utilized for modeling the mechanistic responses in asphalt concrete(AC) layers by simulating...A three dimensional finite element program incorporating actually measured vertical tire-pavement contact pressure(TPCP) was utilized for modeling the mechanistic responses in asphalt concrete(AC) layers by simulating various vehicle motions:stationary and non-stationary(i.e.in acceleration or deceleration mode).Analysis of the results indicated the following items.1) It is critical to use the vertical TPCP as the design control criteria for the tensile strains at the bottom of the AC layer when the base layer modulus is lower in magnitude(e.g.≤400 MPa);however,when the base layer modulus is higher in magnitude(e.g.≥7 000 MPa),the horizontal TPCP and the tensile strains in the X-direction at the surface of the AC layer should also be considered as part of the design response criteria.2) The definition of "overload" needs to be revised to include tire pressure over-inflation,i.e.,a vehicle should be considered to be overloaded if the wheel load exceeds the specification and/or the tire inflation pressure is higher than the specification.3) Light trucks have more structural impact on the strain responses and pavement design when the thickness of the surfacing AC layer is thinner(e.g.≤50 mm).4) The acceleration of a vehicle does not significantly impact the AC surface distresses such as rutting at the top of the upgrade slopes or intersections;however,vehicle deceleration can dramatically induce horizontal shear strains and consequently,aggravate shoving and rutting problems at the highway intersections.Evidently,these factors should be taken into account during mechanistic stress-strain modeling and structural design of asphalt pavements.展开更多
Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular function...Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of m TOR(m TORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immu-nological tolerance. In this review, we describe the mechanisms by which inhibitors of m TOR induce sup-pression by regulation of these pathways at different levels of the immune response. In addition, we par-ticularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of m TOR.展开更多
Understanding the drifting motion of a small semi-submersible drifter is of vital importance regarding monitoring surface currents and the floating pollutants in coastal regions. This work addresses this issue by esta...Understanding the drifting motion of a small semi-submersible drifter is of vital importance regarding monitoring surface currents and the floating pollutants in coastal regions. This work addresses this issue by establishing a mechanistic drifting forecast model based on kinetic analysis. Taking tide–wind–wave into consideration, the forecast model is validated against in situ drifting experiment in the Radial Sand Ridges. Model results show good performance with respect to the measured drifting features, characterized by migrating back and forth twice a day with daily downwind displacements. Trajectory models are used to evaluate the influence of the individual hydrodynamic forcing. The tidal current is the fundamental dynamic condition in the Radial Sand Ridges and has the greatest impact on the drifting distance. However, it loses its leading position in the field of the daily displacement of the used drifter. The simulations reveal that different hydrodynamic forces dominate the daily displacement of the used drifter at different wind scales. The wave-induced mass transport has the greatest influence on the daily displacement at Beaufort wind scale 5–6; while wind drag contributes mostly at wind scale 2–4.展开更多
BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) a...BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma(HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHPassociated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS). Cellbased experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP(0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay.Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction(RT-qPCR), respectively.Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway.Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry:Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose-and timedependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract(0.625mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins(e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3.Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.展开更多
Three sets of data from the field experiments with different wheat( Triticum L. ) varieties and sowing dates in China and USA were used to test the performance of the mechanistic model of wheat development. The result...Three sets of data from the field experiments with different wheat( Triticum L. ) varieties and sowing dates in China and USA were used to test the performance of the mechanistic model of wheat development. The results showed that the absolute prediction errors for most phasic and phenological stages ranged within 0 - 5 days, and the root mean square errors were generally less than 5 days. The model was of high accuracy and low error especially for emergence, tillering, stamen and pistil initiation, and heading stages, reflecting an enhanced level of mechanism and prediction.展开更多
The impact of lipophilicity as represented by the logarithm of octanol/water partition coefficient (logP), the combined steric/polarizability effect as represented by molar refractivity (MR) and bulk as represented by...The impact of lipophilicity as represented by the logarithm of octanol/water partition coefficient (logP), the combined steric/polarizability effect as represented by molar refractivity (MR) and bulk as represented by molar volume (MV) on the biological activity of 29 known aminopyrimidoisoquinolinequinones APIQ were analyzed using quantitative structure activity relationships methodology (QSAR). The activity data chosen was the inhibitory concentration (IC50) against human gastric adenocarcinoma (AGS) cell line. On running regression analysis, the physicochemical parameters and IC50 show very weak correlations as evident by the low values of Pearson Correlation R2 (0.1 to 0.2). Since the individual compounds show appreciable activity (ranging from 20 to 0.5 μM), classification was resorted to in order to expose mechanistic nesting subgroups. This was done by clustering data points around various trend lines extracted from the scattered plot relating parameters to activity using R2 as an index. The correlation of IC50 versus MV was chosen a base of classification owing to higher statistical metrics it yield. This gave five regression lines, each of which is believed to represent a separate mechanistic profile. Additional descriptors were used to consolidate the clustering approach and to give depth to the assumed mechanistic profiles of each cluster.展开更多
Some mechanistic models have been proposed to predict the No3- concentrations in the soil solution at root surface and the NO3-N uptake by plants, but all these relatively effective non-steady state models have not ye...Some mechanistic models have been proposed to predict the No3- concentrations in the soil solution at root surface and the NO3-N uptake by plants, but all these relatively effective non-steady state models have not yet been verified by any soil culture experiment. In the present study, a mathematical model based on the nutrient transport to the roots, root length and root uptake kinetics as well as taking account of the inter-root competition was used for calculation, and soil culture experiments with rice, wheat and rape plants grown on alkali, neutral and acid soils in rhizoboxes with nylon screen as a isolator were carried out to evaluate the prediction ability of the model through comparing the measured NO3-concentrations at root surface and N uptake with the calculated values. Whether the inter-root competition for nutrients was accounted for in the model was of less importance to the calculated N uptake but could induce significant changes in the relative concentrations of NO3- at root surface. For the three soils and crops, the measured NO3-N uptake agreed well with the calculated one, and the calculated relative concentrations at root surface were approximate to the measured values. But an appropriate rectification for some conditions is necessary when the plant uptake parameter obtained in solution culture experiment is applied to soil culture. In contrast with the present non-steady state model, the predicted relative concentrations, which show an accumulation, by the Phillips' steady-state model were distinct from the measured values which show a depletion, indicating that the present model has a better prediction ability than the steady-state model.展开更多
Over past decades,takotsubo cardiomyopathy(TTC)has drawn a substantial interest as a unique form of acute and reversible cardiomyopathy that usually emerges in response to adrenergic hyperactivation associated with a ...Over past decades,takotsubo cardiomyopathy(TTC)has drawn a substantial interest as a unique form of acute and reversible cardiomyopathy that usually emerges in response to adrenergic hyperactivation associated with a variety of emotional and physical triggers.[1,2]Even though,this phenomenon is generally characterized by an apical balloning pattern(classical variant),it might occasionally present with atypical morphological variants including mid-ventricular,inverted and focal forms of myocardial involvement.展开更多
This research aimed to combine 3 cell and tissue culture technologies to obtain mechanistic insights of cells in porous scaffolds. When cultivated on 2D (2-dimensional) surfaces, HDFs (human dermal fibroblasts) be...This research aimed to combine 3 cell and tissue culture technologies to obtain mechanistic insights of cells in porous scaffolds. When cultivated on 2D (2-dimensional) surfaces, HDFs (human dermal fibroblasts) behaved individually and had no strict requirement on seeding density for proliferation; while HaCat cells relied heavily on initial densities for proliferation and colony formation, which was facilitated when co-cultured with HDFs. Experiments using a 3D CCIS (3-dimensional cell culture and imaging system) indicated that HDFs colonised openpores of varying sizes (125-420 ~tm) on modular substrates via bridge structures; while HaCat cells formed aperture structures and only colonised small pores (125 txm). When co-cultured, HDFs not only facilitated HaCat attachment on the substrates, but also coordinated with HaCat cells to colonise open pores of varying sizes via bridge and aperture structures. Based on these observations, a 2-stage strategy for the culture of HDFs and HaCat cells on porous scaffolds was proposed and applied successfully on a cellulosic scaffold. This research demonstrated that cell colonisation in scaffolds was dependent on multiple factors; while the integrated 2D&3D culture technologies and the 3D CCIS was an effective and efficient approach to obtain mechanistic insights of their influences on tissue regeneration.展开更多
Model-based controllers can significantly improve the performance of Proton Exchange Membrane Fuel Cell (PEMFC) systems. However, the complexity of these strategies constraints large scale implementation. In this work...Model-based controllers can significantly improve the performance of Proton Exchange Membrane Fuel Cell (PEMFC) systems. However, the complexity of these strategies constraints large scale implementation. In this work, with a view to reduce complexity without affecting performance, two different modeling approaches of a single-cell PEMFC are investigated. A mechanistic model, describing all internal phenomena in a single-cell, and an artificial neural network (ANN) model are tested. To perform this work, databases are measured on a pilot plant. The identification of the two models involves the optimization of the operating conditions in order to build rich databases. The two different models benefits and drawbacks are pointed out using statistical error criteria. Regarding model-based control approach, the computational time of these models is compared during the validation step.展开更多
The atom-economical cycloaddition of CO_(2) with epoxides to synthesize cyclic carbonates is a promising route for valuable utilization of CO_(2).Halogenide such as alkali metal halides and quaternary ammonium salt ha...The atom-economical cycloaddition of CO_(2) with epoxides to synthesize cyclic carbonates is a promising route for valuable utilization of CO_(2).Halogenide such as alkali metal halides and quaternary ammonium salt have been developed as the efficient catalysts.However,the spilled halogen causes equipment corrosion and affects the product purity.To address these concerns,the halogen-free cycloaddition of CO_(2) with epoxides has always been desired.In this review,we systematically discussed the halogen-free catalysis for cycloaddition of CO_(2) with epoxides from the mechanistic insights,aiming to promote the development of efficient halogen-free catalysts.Two types of catalysts,i.e.,alternatives of halogen nucleophiles for epoxide activation,and bifunctional catalysts with Lewis acid-base sites for synergistic activation of CO_(2) and epoxides are summarized and emphasized.Specially,metal oxides as the potential halogen-free catalysts are highlighted due to their flexible acid-base sites for synergistic activation of CO_(2) and epoxides,facile preparation,and low cost.展开更多
Enhancing hepatic gluconeogenesis is one of the main modes of meeting the glucose requirement of dairy cows.This study attempted to determine whether the gluconeogenesis precursor propionate had an effect on the expre...Enhancing hepatic gluconeogenesis is one of the main modes of meeting the glucose requirement of dairy cows.This study attempted to determine whether the gluconeogenesis precursor propionate had an effect on the expression of the main genes involved in gluconeogenesis in calf hepatocytes and elucidate the associated mechanisms.Calf hepatocytes were obtained from 5 healthy calves(1 d old;30to 40 kg)and exposed to 0-,1-,2.5-,or 5-mM sodium propionate(NaP),which is known to promote the expression of genes involved in the gluconeogenesis pathway,including fructose 1,6-bisphosphatase,phosphoenolpyruvate carboxykinase,and glucose-6-phosphatase.With regard to the underlying mechanism,propionate promoted the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha,hepatocyte nuclear factor 4,and forkhead box O1(transcription factors that regulate the expression of hepatic gluconeogenic genes)by promoting mammalian target of rapamycin complex 1(mTORC1),but inhibiting mTORC2 activity(P<0.01).We also established a model of palmitic acid(PA)-induced hepatic injury in calf hepatocytes and found that PA could inhibit the gluconeogenic capacity of calf hepatocytes by suppressing the expression of gluconeogenic genes,inhibiting m TORC1,and promoting the activity of m TORC2(P<0.01).In contrast,NaP provided protection to calf hepatocytes by counteracting the inhibitory effect of PA on the gluconeogenic capacity of calf hepatocytes(P<0.05).Collectively,these findings indicate that NaP enhances the gluconeogenic capacity of calf hepatocytes by regulating the mTOR pathway activity.Thus,in addition to improving the glucose production potential,propionate may have therapeutic potential for the treatment of hepatic injury in dairy cows.展开更多
BACKGROUND Monopolar spindle-binding protein 3B(MOB3B)functions as a signal transducer and altered MOB3B expression is associated with the development of human cancers.AIM To investigate the role of MOB3B in colorecta...BACKGROUND Monopolar spindle-binding protein 3B(MOB3B)functions as a signal transducer and altered MOB3B expression is associated with the development of human cancers.AIM To investigate the role of MOB3B in colorectal cancer(CRC).METHODS This study collected 102 CRC tissue samples for immunohistochemical detection of MOB3B expression for association with CRC prognosis.After overexpression and knockdown of MOB3B expression were induced in CRC cell lines,changes in cell viability,migration,invasion,and gene expression were assayed.Tumor cell autophagy was detected using transmission electron microscopy,while nude mouse xenograft experiments were performed to confirm the in-vitro results.RESULTS MOB3B expression was reduced in CRC vs normal tissues and loss of MOB3B expression was associated with poor CRC prognosis.Overexpression of MOB3B protein in vitro attenuated the cell viability as well as the migration and invasion capacities of CRC cells,whereas knockdown of MOB3B expression had the opposite effects in CRC cells.At the molecular level,microtubule-associated protein light chain 3 II/I expression was elevated,whereas the expression of matrix metalloproteinase(MMP)2,MMP9,sequestosome 1,and phosphorylated mechanistic target of rapamycin kinase(mTOR)was downregulated in MOB3B-overexpressing RKO cells.In contrast,the opposite results were observed in tumor cells with MOB3B knockdown.The nude mouse data confirmed these in-vitro findings,i.e.,MOB3B expression suppressed CRC cell xenograft growth,whereas knockdown of MOB3B expression promoted the growth of CRC cell xenografts.CONCLUSION Loss of MOB3B expression promotes CRC development and malignant behaviors,suggesting a potential tumor suppressive role of MOB3B in CRC by inhibition of mTOR/autophagy signaling.展开更多
BACKGROUND Osteoporosis(OP)has become a major public health problem worldwide.Most OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing ...BACKGROUND Osteoporosis(OP)has become a major public health problem worldwide.Most OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing osteogenesis.In the bone marrow(BM)niche,bone mesenchymal stem cells(BMSCs)are exposed to a hypoxic environment.Recently,a few studies have demonstrated that hypoxiainducible factor 2alpha(HIF-2α)is involved in BMSC osteogenic differentiation,but the molecular mechanism involved has not been determined.AIM To investigate the effect of HIF-2αon the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells(HSCs)in the BM niche on the progression of OP.METHODS Mice with BMSC-specific HIF-2αknockout(Prx1-Cre;Hif-2αfl/fl mice)were used for in vivo experiments.Bone quantification was performed on mice of two genotypes with three interventions:Bilateral ovariectomy,semilethal irradiation,and dexamethasone treatment.Moreover,the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes.In vitro,the HIF-2αagonist roxadustat and the HIF-2αinhibitor PT2399 were used to investigate the function of HIF-2αin BMSC osteogenic and adipogenic differentiation.Finally,we investigated the effect of HIF-2αon BMSCs via treatment with the mechanistic target of rapamycin(mTOR)agonist MHY1485 and the mTOR inhibitor rapamycin.RESULTS The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions.In vitro,Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2αagonist roxadustat,and after 7 d of BMSC adipogenic differentiation,the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased;in addition,after 14 d of osteogenic differentiation,BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes.The opposite effects were shown for mouse BMSCs treated with the HIF-2αinhibitor PT2399.The mTOR inhibitor rapamycin was used to confirm that HIF-2αregulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway.Consequently,there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice.CONCLUSION Our study showed that inhibition of HIF-2αdecreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.展开更多
BACKGROUND Serpin peptidase inhibitor clade H member 1(SERPINH1)was initially recognized as an oncogene implicated in various human malignancies.Nevertheless,the clinical relevance and functional implications of SERPI...BACKGROUND Serpin peptidase inhibitor clade H member 1(SERPINH1)was initially recognized as an oncogene implicated in various human malignancies.Nevertheless,the clinical relevance and functional implications of SERPINH1 in colorectal cancer(CRC)remain largely elusive.AIM To investigate the effects of SERPINH1 on CRC cells and its specific mechanism.METHODS Quantitative real-time polymerase chain reaction,western blotting analysis,The Cancer Genome Atlas data mining and immunohistochemistry were employed to examine SERPINH1 expression in CRC cell lines and tissues.A series of in-vitro assays were performed to demonstrate the function of SERPINH1 and its possible mechanisms in CRC.RESULTS SERPINH1 demonstrated elevated expression levels in both CRC cells and tissues,manifested at both mRNA and protein tiers.Elevated SERPINH1 levels correlated closely with advanced T stage,lymph node involvement,and distant metastasis,exhibiting a significant association with poorer overall survival among CRC patients.Subsequent investigations unveiled that SERPINH1 overexpression notably bolstered CRC cell proliferation,invasion,and migration in vitro,while conversely,SERPINH1 knockdown elicited the opposite effects.Gene set enrichment analysis underscored a correlation between SERPINH1 upregulation and genes associated with cell cycle regulation.Our findings underscored the capacity of heightened SERPINH1 levels to expedite G1/S phase cell cycle progression via phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway activation,thereby facilitating CRC cell invasion and migration.CONCLUSION These findings imply a crucial involvement of SERPINH1 in the advancement and escalation of CRC,potentially positioning it as a novel candidate for prognostic assessment and therapeutic intervention in CRC management.展开更多
To predict global climate change and to implement the Kyoto Protocol for stabilizing atmospheric greenhouse gases concentrations require quantifying spatio-temporal variations in the terrestrial carbon sink accurately...To predict global climate change and to implement the Kyoto Protocol for stabilizing atmospheric greenhouse gases concentrations require quantifying spatio-temporal variations in the terrestrial carbon sink accurately. During the past decade multi-scale ecological experiment and observation networks have been established using various new technologies (e.g. controlled environmental facilities, eddy covariance techniques and quantitative remote sensing), and have obtained a large amount of data about terrestrial ecosystem carbon cycle. However, uncertainties in the magnitude and spatio-temporal variations of the terrestrial carbon sink and in understanding the underlying mechanisms have not been reduced significantly. One of the major reasons is that the observations and experiments were conducted at individual scales independently, but it is the interactions of factors and processes at different scales that determine the dynamics of the terrestrial carbon sink. Since experiments and observations are always conducted at specific scales, to understand cross-scale interactions requires mechanistic analysis that is best to be achieved by mechanistic modeling. However, mechanistic ecosystem models are mainly based on data from single-scale experiments and observations and hence have no capacity to simulate mechanistic cross-scale interconnection and interactions of ecosystem processes. New-generation mechanistic ecosystem models based on new ecological theoretical framework are needed to quantify the mechanisms from micro-level fast eco-physiological responses to macro-level slow acclimation in the pattern and structure in disturbed ecosystems. Multi-scale data-model fusion is a recently emerging approach to assimilate multi-scale observational data into mechanistic, dynamic modeling, in which the structure and parameters of mechanistic models for simulating cross-scale interactions are optimized using multi-scale observational data. The models are validated and evaluated at different spatial and temporal scales and real-time observational data are assimilated continuously into dynamic modeling for predicting and forecasting ecosystem changes realistically. in summary, a breakthrough in terrestrial carbon sink research requires using approaches of multi-scale observations and cross-scale modeling to understand and quantify interconnections and interactions among ecosystem processes at different scales and their controls over ecosystem carbon cycle.展开更多
An improved method to determine cutting force coefficients for bull-nose cutters is proposed based on the semi-mechanistic cutting force model. Due to variations of cutting speed along the tool axis in bull-nose milli...An improved method to determine cutting force coefficients for bull-nose cutters is proposed based on the semi-mechanistic cutting force model. Due to variations of cutting speed along the tool axis in bull-nose milling, they affect coefficients significantly and may bring remarkable discrepancies in the prediction of cutting forces. Firstly, the bull-nose cutter is regarded as a finite number of axial discs piled up along the tool axis, and the rigid cutting force model is exerted. Then through discretization along cutting edges, the cutting force related to each element is recalculated, which equals to differential force value between the current and previous elements. In addition, coefficient identification adopts the cubic polynomial fitting method with the slice elevation as its horizontal axis. By calculating relations of cutting speed and cutting depth, the influences of speed variations on cutting force can be derived. Thereby, several tests are conducted to calibrate the coefficients using the improved method, which are applied to later force predictions. Eventually, experimental evaluations are discussed to verify the effectiveness. Compared to the conventional method, the results are more accurate and show satisfactory consistency with the simulations. For further applications, the method is instructive to predict the cutting forces in bull-nose milling with lead or tilt angles and can be extended to the selection of cutting parameters.展开更多
The synthesis of highly uniform alloy nanocrystals with a concave feature is desirable for applications in catalysis but is an arduous task. This article proposes an initiative protocol for the fabrication of novel Cu...The synthesis of highly uniform alloy nanocrystals with a concave feature is desirable for applications in catalysis but is an arduous task. This article proposes an initiative protocol for the fabrication of novel Cu-Pd alloy nanocrystals, wherein the volume of decylamine (DA) in the reaction system was found to greatly influence the formation of different morphologies, including the tetrahedron (TH), concave tetrahedron (CTH), rhombohedral-tetrapod (RTP), and tetrapod (TP). The alloy structure of the products arises from the coordination interaction between the DA and metal ions, which affects the reduction potential of Cu and Pd species, and thus yields co-reduction. Other reaction parameters, such as the type of ligand, amount of reductant, and temperature, were also altered to study the growth mechanism, yielding consistent conclusions in the diffusion-controlled regime. As a catalyst, 48-nm Cu-Pd concave tetrahedral nanocrystals were highly active for the hydrogenation of 3-nitrostyrene and exhibited 〉99.9% chemoselectivity to C=C instead of-NO2.展开更多
基金the Natural Science Foundation of China(Grant No:22309180)Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No:XDB0600000,XDB0600400)+3 种基金Liaoning Binhai Laboratory,(Grant No:LILBLB-2023-04)Dalian Revitalization Talents Program(Grant No:2022RG01)Youth Science and Technology Foundation of Dalian(Grant No:2023RQ015)the University of Waterloo.
文摘Zinc-air batteries(ZABs)are promising energy storage systems because of high theoretical energy density,safety,low cost,and abundance of zinc.However,the slow multi-step reaction of oxygen and heavy reliance on noble-metal catalysts hinder the practical applications of ZABs.Therefore,feasible and advanced non-noble-metal elec-trocatalysts for air cathodes need to be identified to promote the oxygen catalytic reaction.In this review,we initially introduced the advancement of ZABs in the past two decades and provided an overview of key developments in this field.Then,we discussed the work-ing mechanism and the design of bifunctional electrocatalysts from the perspective of morphology design,crystal structure tuning,interface strategy,and atomic engineering.We also included theoretical studies,machine learning,and advanced characterization technologies to provide a comprehensive understanding of the structure-performance relationship of electrocatalysts and the reaction pathways of the oxygen redox reactions.Finally,we discussed the challenges and prospects related to designing advanced non-noble-metal bifunctional electrocatalysts for ZABs.
文摘Colorectal cancer(CRC)is a common cancer with high morbidity and mortality rates.Its occurrence and development are determined by many factors,including genetics,the environment,lifestyle,and so on.The occurrence of CRC is often accompanied by changes in the intestinal microenvironment.Numerous studies have focused on the association between dietary patterns,dietary components,and CRC now.This article reviews five different dietary patterns:the Western diet,the Mediterranean diet,the ketogenic diet,the Dietary Approaches to Stop Hypertension diet,and fasting,and themechanistic associations between their food components and CRC.The finding can provide a reference for further studies on the association between different dietary patterns and CRC and will help clinicians formulate reasonable and feasible dietary interventions.
文摘A three dimensional finite element program incorporating actually measured vertical tire-pavement contact pressure(TPCP) was utilized for modeling the mechanistic responses in asphalt concrete(AC) layers by simulating various vehicle motions:stationary and non-stationary(i.e.in acceleration or deceleration mode).Analysis of the results indicated the following items.1) It is critical to use the vertical TPCP as the design control criteria for the tensile strains at the bottom of the AC layer when the base layer modulus is lower in magnitude(e.g.≤400 MPa);however,when the base layer modulus is higher in magnitude(e.g.≥7 000 MPa),the horizontal TPCP and the tensile strains in the X-direction at the surface of the AC layer should also be considered as part of the design response criteria.2) The definition of "overload" needs to be revised to include tire pressure over-inflation,i.e.,a vehicle should be considered to be overloaded if the wheel load exceeds the specification and/or the tire inflation pressure is higher than the specification.3) Light trucks have more structural impact on the strain responses and pavement design when the thickness of the surfacing AC layer is thinner(e.g.≤50 mm).4) The acceleration of a vehicle does not significantly impact the AC surface distresses such as rutting at the top of the upgrade slopes or intersections;however,vehicle deceleration can dramatically induce horizontal shear strains and consequently,aggravate shoving and rutting problems at the highway intersections.Evidently,these factors should be taken into account during mechanistic stress-strain modeling and structural design of asphalt pavements.
基金Supported by Novartis Espana and by grant to Pons JA as Principal Investigator from Instituto Salud Carlos III,No.PI12/02042
文摘Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of m TOR(m TORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immu-nological tolerance. In this review, we describe the mechanisms by which inhibitors of m TOR induce sup-pression by regulation of these pathways at different levels of the immune response. In addition, we par-ticularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of m TOR.
基金supported by the National Key Research and Development Program of China(Grant No.2017YFC0405401)the National Science&Technology Pillar Program(Grant No.2012BAB03B01)+1 种基金the Fundamental Research Funds for the Central Universities,Hohai University(Grant No.2014B30914)the Natural Science Foundation of Jiangsu Province(Grant No.BK2012411)
文摘Understanding the drifting motion of a small semi-submersible drifter is of vital importance regarding monitoring surface currents and the floating pollutants in coastal regions. This work addresses this issue by establishing a mechanistic drifting forecast model based on kinetic analysis. Taking tide–wind–wave into consideration, the forecast model is validated against in situ drifting experiment in the Radial Sand Ridges. Model results show good performance with respect to the measured drifting features, characterized by migrating back and forth twice a day with daily downwind displacements. Trajectory models are used to evaluate the influence of the individual hydrodynamic forcing. The tidal current is the fundamental dynamic condition in the Radial Sand Ridges and has the greatest impact on the drifting distance. However, it loses its leading position in the field of the daily displacement of the used drifter. The simulations reveal that different hydrodynamic forces dominate the daily displacement of the used drifter at different wind scales. The wave-induced mass transport has the greatest influence on the daily displacement at Beaufort wind scale 5–6; while wind drag contributes mostly at wind scale 2–4.
基金Supported by National Natural Science Foundation of China, No. U20A20408 and No. 82074450Natural Science Foundation of Hunan Province, No. 2020JJ4066+4 种基金Hunan Province"Domestic First-class Cultivation Discipline"Integrated Traditional Chinese and Western Medicine Open Fund Project, No. 2020ZXYJH34 and No. 2020ZXYJH35Hunan Graduate Scientific Research Innovation Project, No. QL20210173 and No. CX20210730Hunan Province Science and Technology Innovation Talents Plan College Students Science and Technology Innovation and Entrepreneurship Project, No. 2020RC1004Guangzhou Health Science and Technology Project, No. 20221A011102Hunan Traditional Chinese Medicine Scientific Research Project, No. 202101
文摘BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma(HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHPassociated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS). Cellbased experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP(0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay.Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction(RT-qPCR), respectively.Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway.Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry:Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose-and timedependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract(0.625mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins(e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3.Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.
文摘Three sets of data from the field experiments with different wheat( Triticum L. ) varieties and sowing dates in China and USA were used to test the performance of the mechanistic model of wheat development. The results showed that the absolute prediction errors for most phasic and phenological stages ranged within 0 - 5 days, and the root mean square errors were generally less than 5 days. The model was of high accuracy and low error especially for emergence, tillering, stamen and pistil initiation, and heading stages, reflecting an enhanced level of mechanism and prediction.
文摘The impact of lipophilicity as represented by the logarithm of octanol/water partition coefficient (logP), the combined steric/polarizability effect as represented by molar refractivity (MR) and bulk as represented by molar volume (MV) on the biological activity of 29 known aminopyrimidoisoquinolinequinones APIQ were analyzed using quantitative structure activity relationships methodology (QSAR). The activity data chosen was the inhibitory concentration (IC50) against human gastric adenocarcinoma (AGS) cell line. On running regression analysis, the physicochemical parameters and IC50 show very weak correlations as evident by the low values of Pearson Correlation R2 (0.1 to 0.2). Since the individual compounds show appreciable activity (ranging from 20 to 0.5 μM), classification was resorted to in order to expose mechanistic nesting subgroups. This was done by clustering data points around various trend lines extracted from the scattered plot relating parameters to activity using R2 as an index. The correlation of IC50 versus MV was chosen a base of classification owing to higher statistical metrics it yield. This gave five regression lines, each of which is believed to represent a separate mechanistic profile. Additional descriptors were used to consolidate the clustering approach and to give depth to the assumed mechanistic profiles of each cluster.
文摘Some mechanistic models have been proposed to predict the No3- concentrations in the soil solution at root surface and the NO3-N uptake by plants, but all these relatively effective non-steady state models have not yet been verified by any soil culture experiment. In the present study, a mathematical model based on the nutrient transport to the roots, root length and root uptake kinetics as well as taking account of the inter-root competition was used for calculation, and soil culture experiments with rice, wheat and rape plants grown on alkali, neutral and acid soils in rhizoboxes with nylon screen as a isolator were carried out to evaluate the prediction ability of the model through comparing the measured NO3-concentrations at root surface and N uptake with the calculated values. Whether the inter-root competition for nutrients was accounted for in the model was of less importance to the calculated N uptake but could induce significant changes in the relative concentrations of NO3- at root surface. For the three soils and crops, the measured NO3-N uptake agreed well with the calculated one, and the calculated relative concentrations at root surface were approximate to the measured values. But an appropriate rectification for some conditions is necessary when the plant uptake parameter obtained in solution culture experiment is applied to soil culture. In contrast with the present non-steady state model, the predicted relative concentrations, which show an accumulation, by the Phillips' steady-state model were distinct from the measured values which show a depletion, indicating that the present model has a better prediction ability than the steady-state model.
文摘Over past decades,takotsubo cardiomyopathy(TTC)has drawn a substantial interest as a unique form of acute and reversible cardiomyopathy that usually emerges in response to adrenergic hyperactivation associated with a variety of emotional and physical triggers.[1,2]Even though,this phenomenon is generally characterized by an apical balloning pattern(classical variant),it might occasionally present with atypical morphological variants including mid-ventricular,inverted and focal forms of myocardial involvement.
文摘This research aimed to combine 3 cell and tissue culture technologies to obtain mechanistic insights of cells in porous scaffolds. When cultivated on 2D (2-dimensional) surfaces, HDFs (human dermal fibroblasts) behaved individually and had no strict requirement on seeding density for proliferation; while HaCat cells relied heavily on initial densities for proliferation and colony formation, which was facilitated when co-cultured with HDFs. Experiments using a 3D CCIS (3-dimensional cell culture and imaging system) indicated that HDFs colonised openpores of varying sizes (125-420 ~tm) on modular substrates via bridge structures; while HaCat cells formed aperture structures and only colonised small pores (125 txm). When co-cultured, HDFs not only facilitated HaCat attachment on the substrates, but also coordinated with HaCat cells to colonise open pores of varying sizes via bridge and aperture structures. Based on these observations, a 2-stage strategy for the culture of HDFs and HaCat cells on porous scaffolds was proposed and applied successfully on a cellulosic scaffold. This research demonstrated that cell colonisation in scaffolds was dependent on multiple factors; while the integrated 2D&3D culture technologies and the 3D CCIS was an effective and efficient approach to obtain mechanistic insights of their influences on tissue regeneration.
文摘Model-based controllers can significantly improve the performance of Proton Exchange Membrane Fuel Cell (PEMFC) systems. However, the complexity of these strategies constraints large scale implementation. In this work, with a view to reduce complexity without affecting performance, two different modeling approaches of a single-cell PEMFC are investigated. A mechanistic model, describing all internal phenomena in a single-cell, and an artificial neural network (ANN) model are tested. To perform this work, databases are measured on a pilot plant. The identification of the two models involves the optimization of the operating conditions in order to build rich databases. The two different models benefits and drawbacks are pointed out using statistical error criteria. Regarding model-based control approach, the computational time of these models is compared during the validation step.
基金Financial support from the National Key R&D Program of China(Grant No.2022YFB4101900)National Natural Science Foundation of China(Grant Nos.22278305 and U21B2096).
文摘The atom-economical cycloaddition of CO_(2) with epoxides to synthesize cyclic carbonates is a promising route for valuable utilization of CO_(2).Halogenide such as alkali metal halides and quaternary ammonium salt have been developed as the efficient catalysts.However,the spilled halogen causes equipment corrosion and affects the product purity.To address these concerns,the halogen-free cycloaddition of CO_(2) with epoxides has always been desired.In this review,we systematically discussed the halogen-free catalysis for cycloaddition of CO_(2) with epoxides from the mechanistic insights,aiming to promote the development of efficient halogen-free catalysts.Two types of catalysts,i.e.,alternatives of halogen nucleophiles for epoxide activation,and bifunctional catalysts with Lewis acid-base sites for synergistic activation of CO_(2) and epoxides are summarized and emphasized.Specially,metal oxides as the potential halogen-free catalysts are highlighted due to their flexible acid-base sites for synergistic activation of CO_(2) and epoxides,facile preparation,and low cost.
基金supported by the National Natural Science Foundation of China(grant numbers 32070782,32072761,32100578)the Guangdong Basic and Applied Basic Research Foundation(grant number 2021A1515220036).
文摘Enhancing hepatic gluconeogenesis is one of the main modes of meeting the glucose requirement of dairy cows.This study attempted to determine whether the gluconeogenesis precursor propionate had an effect on the expression of the main genes involved in gluconeogenesis in calf hepatocytes and elucidate the associated mechanisms.Calf hepatocytes were obtained from 5 healthy calves(1 d old;30to 40 kg)and exposed to 0-,1-,2.5-,or 5-mM sodium propionate(NaP),which is known to promote the expression of genes involved in the gluconeogenesis pathway,including fructose 1,6-bisphosphatase,phosphoenolpyruvate carboxykinase,and glucose-6-phosphatase.With regard to the underlying mechanism,propionate promoted the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha,hepatocyte nuclear factor 4,and forkhead box O1(transcription factors that regulate the expression of hepatic gluconeogenic genes)by promoting mammalian target of rapamycin complex 1(mTORC1),but inhibiting mTORC2 activity(P<0.01).We also established a model of palmitic acid(PA)-induced hepatic injury in calf hepatocytes and found that PA could inhibit the gluconeogenic capacity of calf hepatocytes by suppressing the expression of gluconeogenic genes,inhibiting m TORC1,and promoting the activity of m TORC2(P<0.01).In contrast,NaP provided protection to calf hepatocytes by counteracting the inhibitory effect of PA on the gluconeogenic capacity of calf hepatocytes(P<0.05).Collectively,these findings indicate that NaP enhances the gluconeogenic capacity of calf hepatocytes by regulating the mTOR pathway activity.Thus,in addition to improving the glucose production potential,propionate may have therapeutic potential for the treatment of hepatic injury in dairy cows.
基金Supported by National Natural Science Foundation of China,No.81760516Natural Science Foundation of Guangxi,China,No.2019GXNSFAA185030+1 种基金Self-Financed Scientific Research Projects of Guangxi Zhuang Autonomous Region Health and Family Planning Commission,China,No.Z20181003Guangxi Medical University Youth Science Fund Project,China,No.GXMUYSF202221.
文摘BACKGROUND Monopolar spindle-binding protein 3B(MOB3B)functions as a signal transducer and altered MOB3B expression is associated with the development of human cancers.AIM To investigate the role of MOB3B in colorectal cancer(CRC).METHODS This study collected 102 CRC tissue samples for immunohistochemical detection of MOB3B expression for association with CRC prognosis.After overexpression and knockdown of MOB3B expression were induced in CRC cell lines,changes in cell viability,migration,invasion,and gene expression were assayed.Tumor cell autophagy was detected using transmission electron microscopy,while nude mouse xenograft experiments were performed to confirm the in-vitro results.RESULTS MOB3B expression was reduced in CRC vs normal tissues and loss of MOB3B expression was associated with poor CRC prognosis.Overexpression of MOB3B protein in vitro attenuated the cell viability as well as the migration and invasion capacities of CRC cells,whereas knockdown of MOB3B expression had the opposite effects in CRC cells.At the molecular level,microtubule-associated protein light chain 3 II/I expression was elevated,whereas the expression of matrix metalloproteinase(MMP)2,MMP9,sequestosome 1,and phosphorylated mechanistic target of rapamycin kinase(mTOR)was downregulated in MOB3B-overexpressing RKO cells.In contrast,the opposite results were observed in tumor cells with MOB3B knockdown.The nude mouse data confirmed these in-vitro findings,i.e.,MOB3B expression suppressed CRC cell xenograft growth,whereas knockdown of MOB3B expression promoted the growth of CRC cell xenografts.CONCLUSION Loss of MOB3B expression promotes CRC development and malignant behaviors,suggesting a potential tumor suppressive role of MOB3B in CRC by inhibition of mTOR/autophagy signaling.
基金Supported by Basic and Applied Basic Research Foundation of Guangdong Province,No.2020A1515010123 and No.2021A1515010695Special Fund Project for Science and Technology Innovation Strategy of Guangdong Province,No.2019A030317011.
文摘BACKGROUND Osteoporosis(OP)has become a major public health problem worldwide.Most OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing osteogenesis.In the bone marrow(BM)niche,bone mesenchymal stem cells(BMSCs)are exposed to a hypoxic environment.Recently,a few studies have demonstrated that hypoxiainducible factor 2alpha(HIF-2α)is involved in BMSC osteogenic differentiation,but the molecular mechanism involved has not been determined.AIM To investigate the effect of HIF-2αon the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells(HSCs)in the BM niche on the progression of OP.METHODS Mice with BMSC-specific HIF-2αknockout(Prx1-Cre;Hif-2αfl/fl mice)were used for in vivo experiments.Bone quantification was performed on mice of two genotypes with three interventions:Bilateral ovariectomy,semilethal irradiation,and dexamethasone treatment.Moreover,the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes.In vitro,the HIF-2αagonist roxadustat and the HIF-2αinhibitor PT2399 were used to investigate the function of HIF-2αin BMSC osteogenic and adipogenic differentiation.Finally,we investigated the effect of HIF-2αon BMSCs via treatment with the mechanistic target of rapamycin(mTOR)agonist MHY1485 and the mTOR inhibitor rapamycin.RESULTS The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions.In vitro,Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2αagonist roxadustat,and after 7 d of BMSC adipogenic differentiation,the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased;in addition,after 14 d of osteogenic differentiation,BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes.The opposite effects were shown for mouse BMSCs treated with the HIF-2αinhibitor PT2399.The mTOR inhibitor rapamycin was used to confirm that HIF-2αregulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway.Consequently,there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice.CONCLUSION Our study showed that inhibition of HIF-2αdecreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.
基金Supported by Ruian Natural Science Foundation,No.MS2021008.
文摘BACKGROUND Serpin peptidase inhibitor clade H member 1(SERPINH1)was initially recognized as an oncogene implicated in various human malignancies.Nevertheless,the clinical relevance and functional implications of SERPINH1 in colorectal cancer(CRC)remain largely elusive.AIM To investigate the effects of SERPINH1 on CRC cells and its specific mechanism.METHODS Quantitative real-time polymerase chain reaction,western blotting analysis,The Cancer Genome Atlas data mining and immunohistochemistry were employed to examine SERPINH1 expression in CRC cell lines and tissues.A series of in-vitro assays were performed to demonstrate the function of SERPINH1 and its possible mechanisms in CRC.RESULTS SERPINH1 demonstrated elevated expression levels in both CRC cells and tissues,manifested at both mRNA and protein tiers.Elevated SERPINH1 levels correlated closely with advanced T stage,lymph node involvement,and distant metastasis,exhibiting a significant association with poorer overall survival among CRC patients.Subsequent investigations unveiled that SERPINH1 overexpression notably bolstered CRC cell proliferation,invasion,and migration in vitro,while conversely,SERPINH1 knockdown elicited the opposite effects.Gene set enrichment analysis underscored a correlation between SERPINH1 upregulation and genes associated with cell cycle regulation.Our findings underscored the capacity of heightened SERPINH1 levels to expedite G1/S phase cell cycle progression via phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway activation,thereby facilitating CRC cell invasion and migration.CONCLUSION These findings imply a crucial involvement of SERPINH1 in the advancement and escalation of CRC,potentially positioning it as a novel candidate for prognostic assessment and therapeutic intervention in CRC management.
基金This study was supported by the China's Ministry of Science and Technology(Grant No.G2002CB412507)the National Natural Science Foundation of China(Grant No.40425103).
文摘To predict global climate change and to implement the Kyoto Protocol for stabilizing atmospheric greenhouse gases concentrations require quantifying spatio-temporal variations in the terrestrial carbon sink accurately. During the past decade multi-scale ecological experiment and observation networks have been established using various new technologies (e.g. controlled environmental facilities, eddy covariance techniques and quantitative remote sensing), and have obtained a large amount of data about terrestrial ecosystem carbon cycle. However, uncertainties in the magnitude and spatio-temporal variations of the terrestrial carbon sink and in understanding the underlying mechanisms have not been reduced significantly. One of the major reasons is that the observations and experiments were conducted at individual scales independently, but it is the interactions of factors and processes at different scales that determine the dynamics of the terrestrial carbon sink. Since experiments and observations are always conducted at specific scales, to understand cross-scale interactions requires mechanistic analysis that is best to be achieved by mechanistic modeling. However, mechanistic ecosystem models are mainly based on data from single-scale experiments and observations and hence have no capacity to simulate mechanistic cross-scale interconnection and interactions of ecosystem processes. New-generation mechanistic ecosystem models based on new ecological theoretical framework are needed to quantify the mechanisms from micro-level fast eco-physiological responses to macro-level slow acclimation in the pattern and structure in disturbed ecosystems. Multi-scale data-model fusion is a recently emerging approach to assimilate multi-scale observational data into mechanistic, dynamic modeling, in which the structure and parameters of mechanistic models for simulating cross-scale interactions are optimized using multi-scale observational data. The models are validated and evaluated at different spatial and temporal scales and real-time observational data are assimilated continuously into dynamic modeling for predicting and forecasting ecosystem changes realistically. in summary, a breakthrough in terrestrial carbon sink research requires using approaches of multi-scale observations and cross-scale modeling to understand and quantify interconnections and interactions among ecosystem processes at different scales and their controls over ecosystem carbon cycle.
基金the Postgraduate Seed Fund of Northwestern Polytechnical University(No.Z2012038)National Natural Science Foundation of China(No.51005183)National Key S&T Special Projects(No.2011X04016-031)
文摘An improved method to determine cutting force coefficients for bull-nose cutters is proposed based on the semi-mechanistic cutting force model. Due to variations of cutting speed along the tool axis in bull-nose milling, they affect coefficients significantly and may bring remarkable discrepancies in the prediction of cutting forces. Firstly, the bull-nose cutter is regarded as a finite number of axial discs piled up along the tool axis, and the rigid cutting force model is exerted. Then through discretization along cutting edges, the cutting force related to each element is recalculated, which equals to differential force value between the current and previous elements. In addition, coefficient identification adopts the cubic polynomial fitting method with the slice elevation as its horizontal axis. By calculating relations of cutting speed and cutting depth, the influences of speed variations on cutting force can be derived. Thereby, several tests are conducted to calibrate the coefficients using the improved method, which are applied to later force predictions. Eventually, experimental evaluations are discussed to verify the effectiveness. Compared to the conventional method, the results are more accurate and show satisfactory consistency with the simulations. For further applications, the method is instructive to predict the cutting forces in bull-nose milling with lead or tilt angles and can be extended to the selection of cutting parameters.
文摘The synthesis of highly uniform alloy nanocrystals with a concave feature is desirable for applications in catalysis but is an arduous task. This article proposes an initiative protocol for the fabrication of novel Cu-Pd alloy nanocrystals, wherein the volume of decylamine (DA) in the reaction system was found to greatly influence the formation of different morphologies, including the tetrahedron (TH), concave tetrahedron (CTH), rhombohedral-tetrapod (RTP), and tetrapod (TP). The alloy structure of the products arises from the coordination interaction between the DA and metal ions, which affects the reduction potential of Cu and Pd species, and thus yields co-reduction. Other reaction parameters, such as the type of ligand, amount of reductant, and temperature, were also altered to study the growth mechanism, yielding consistent conclusions in the diffusion-controlled regime. As a catalyst, 48-nm Cu-Pd concave tetrahedral nanocrystals were highly active for the hydrogenation of 3-nitrostyrene and exhibited 〉99.9% chemoselectivity to C=C instead of-NO2.